Cognitive Effects of Rasagiline in Mild-to-Moderate Stage Parkinson's Disease Without Dementia

This interventional study provides class 1 evidence regarding the effect of rasagiline on cognition in nondemented patients with mild-to-moderate stage PD during a 26-week, double-blind, placebo-controlled study.

Fifty participants were recruited from new and existing patients diagnosed with idiopathic PD at the Movement Disorders Clinic at Butler Hospital in Providence, Rhode Island. Forty-five patients completed the study (age: 50–83 years old, mean=68.6 years [SD=8.0]; sex: 34 males, 11 females; education: 8–22 years, mean=15.4 [SD=3.2]; Mini-Mental Status Examination [MMSE] range: 23 to 30/30 points, mean=28.2 [SD=2 points]). Participants enrolled in this study were naive to PD medications, or on levodopa medications, or on dopamine agonist medications. Patients enrolled in the study did not meet DMS-IV criteria for dementia due to PD, were able to speak and read English, had at least 6 years of formal education, were not clinically depressed, had a diagnosis of PD, and had been on stable medication regimens (no new PD medications and no changes to existing PD medication dosages) for the 4 weeks prior to study enrollment. If participants were already taking other Parkinson’s medications at the time of study enrollment, the dosages of those medications remained stable throughout study participation. Changes to existing Parkinson’s medication dosages or addition of other medications to treat PD after study enrollment resulted in removal from study. Participants were allowed to begin non-PD medications or to have changes to their existing non-PD medications if these additions and changes were deemed medically necessary by their providers. Patients were excluded if they were taking any other MAO inhibitor; taking a cognition-enhancing medication, such as a cholinesterase inhibitor medication or memantine; had an MMSE score below 21/30; had significant depression (Beck Depression Inventory−13 item score >7); or had another neurodegenerative disorder besides PD, an unstable cardiac disorder, or clinically significant hepatic, lung, or renal disease.

The study and all procedures were approved by the institutional review boards of Butler Hospital in Providence, Rhode Island, and Memorial Hospital of Rhode Island in Pawtucket, Rhode Island. All patients provided written informed consent.

To facilitate recruitment, we enrolled participants who were of different ages, at various stages of disease severity, and on a variety of different medication regimens. We used statistical methods and urn randomization to control for these differences and ensure that our treatment and control groups were equally balanced on these variables. Following baseline cognitive testing, participants were urn randomized into either the treatment (N=23) or control group (N=22). Urns for this study included Parkinson’s staging and treatment with levodopa or dopamine agonist medications. Thirty-one of our patients were taking a medication for PD at baseline (16 in the treatment group and 15 in the placebo group). Our groups were also balanced on disease staging at baseline using the motor subtest of the Unified Parkinson’s Disease Rating Scale ([UPDRS]⁷ treatment group mean=23.9 [SD=10.7]; placebo group mean=21.7 [SD=9.6]) and the Hoehn-Yahr scale ([H-Y]⁸ treatment group mean=2.0 [SD=0.4]; placebo group mean=1.9 [SD=0.6]).

Prior to study enrollment, participants completed a neurological evaluation, the MMSE, and a self-report measure of depression (Beck Depression Inventory−13 item).⁹ Patients who met the inclusion criteria were invited to participate and provided informed consent. Participants in the treatment group received rasagiline 1 mg per day, while control participants received matching placebo. The duration of the study for each participant was 26 weeks.

Baseline cognitive testing was performed prior to randomization and treatment and repeated after 26 weeks in the study. The neuropsychological battery was chosen to provide a broad assessment of cognition across multiple domains, including attention, executive functioning, language, visuospatial perception, and memory. Attention was assessed using the Digit Span subtest from the Wechsler Adult Intelligence Scale—Fourth edition.¹⁰ Executive functioning was assessed using the Trail Making Test (TMT) A and B,¹¹ the clock drawing test,¹² verbal fluency tests (F-A-S letter fluency and animal naming),¹³ and the Oral Symbol Digit Modalities Test (OSDM).¹⁴ Language was assessed using the 30-item abbreviated version of the Boston Naming Test,¹⁵ visuospatial perception was assessed using the Judgment of Line Orientation from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS),¹⁶ and motor functioning was assessed using the Purdue Pegboard test (bimanual).¹⁷ Memory was assessed using a 15-item word list learning task (Rey Auditory Verbal Learning Test [RAVLT]).¹³ In addition to the initial neurological evaluation, a medical visit was performed at week 12, and a final neurological evaluation was performed at week 26.

All analyses were performed using PASW Statistics 18. Preliminary t tests were performed to ensure that our groups were equivalent on age, MMSE score, and education level. All of these t tests were nonsignifcant; differences in age between our treatment and placebo groups approached, but did not reach, significance (70.7 rasagiline group versus 66.4 placebo group, p<0.068). To test whether rasagiline produced improvements in cognitive functioning, a series of repeated-measures analyses of variance (ANOVAs) of the raw scores were used to compare our treatment and control groups on the above-described cognitive measures at baseline and after 26 weeks of treatment. Additional repeated-measures ANOVAs were used compare UPDRS motor scores from baseline to final assessment.